Phenylketonuria (PKU, OMIM 261600), the most frequent IEM, represents an autosomal recessive spectrum of disorders [25, 26] due to a defect of the phenylalanine hydroxylating system. This spectrum includes classic and mild PKU, due to phenylalanine hydroxylase (PAH) enzyme deficiency, and several forms of hyperphenylalaninemia due to the deficiency of tetrahydrobiopterin (BH₄), a critical PAH co-factor. PAH, in fact, converts phenylalanine (Phe) into tyrosine (Tyr) and requires tetrahydrobiopterin (BH₄) for its activity. The enzyme dysfunction, due to PAH gene mutations, results in intolerance of dietary protein intake with a build up of phenylketones which are toxic for brain development. High brain phenylalanine levels also undermine neurotransmitters biosynthesis, due to the competition with large neutral amino acids uptake through the blood–brain barrier. Besides classic PKU, hyperphenylalaninemia can also be determined by defects in the tetrahydrobiopterin (BH₄) regeneration pathway, which encompasses non-PKU BH₄ responsive hyperphenylalaninemias and other BH₄ metabolism-related disorders (including guanidine triphosphate cyclohydrolase 1 [GTPCH1], 6-pyruvoyltetrahydropterin synthase [PTPS], and dihydropteridin reductase [DHPR] deficiency), which will not be discussed in this chapter. Only GTPCH1 deficiency will be further described due to its clinical peculiarity and responsiveness to treatment.

1:10,000 births in Europe

In classical PKU, the clinical picture is greatly related to the severity of enzyme deficiency and Phe levels.

Untreated patients show decreased skin, hair, and iris pigmentation (due to tyrosinase inhibition effect); musty body odor and eczema (due to high phenylalanine and phenylalanine metabolites excretion); secondary microcephaly; delayed psychomotor development/mental retardation; epilepsy; movement disorders and para/hemiparesis; behavioral and psychiatric disorders.

Treated patients with persistent hyperphenylalaninemia or with treatment poor compliance develop: suboptimal cognitive outcome; tremor, increased muscle tone; psychiatric problems; osteopenia and low bone mineral density; vitamin B₁₂ deficiency.

PKU patients that strictly follow dietary treatment suggestions and present a good biochemical control and patients with milder forms of the disease display a nearly asymptomatic clinical course. These patients show no or subtle neurological and psychological symptoms mostly represented by brisk tendon reflexes, tremor, hyperhidrosis, school difficulties, anxiety, and phobias.

These clinical findings are also reported in adult PKU patients.

PKU is usually diagnosed by newborn screening and confirmed by plasma amino acid analysis.

Brain MRI – White matter involvement (WMI) has been largely reported in PKU patients together with volumetric alterations in basal ganglia, somehow related to dopamine pathway dysfunction [27, 28].

Hyperphenylalaninemia (HPA) can be due to defects in BH₄ metabolism, which represents almost 3–5% of HPA. To rule out a BH₄ defect, pterins analysis in urine or blood spots and DHPR enzyme activity in erythrocytes should be performed.

A dietary restriction in Phe intake must be started at the diagnosis. BH₄ loading test should be performed in all patients to ascertain who can benefit from this therapy. In patients who respond to BH_4, the diet can be relaxed or discontinued [29]. At any age [30], the main goal is to achieve a Phe level <360 μmol/L. Dietary restriction must be adapted over the years and according with personal Phe tolerance. Other therapeutic options include large neutral amino acids (LNAA) supplementation, enzyme replacement therapy (providing the administration of modified phenylalanine ammonia lyase, now in phase III study), and somatic gene therapy [31–33].

The prognosis is excellent in patients diagnosed by neonatal screening and treated continuously from birth.

The picture of adult PKU patients and their long-term outcome is still controversial. In early treated PKU adults, impairment of selective and sustained attention and working memory have been reported. Moreover, the role of the brain MRI in identifying white matter lesions is still debated although several recent studies showed a strict relation between high Phe levels and brain lesions [34].

Guanosine triphosphate cyclohydrolase 1 deficiency (GTPCH1, OMIM 600225) comprise a continuum of autosomal dominant (AD) or autosomal recessive (AR) inherited disorders [36] of biogenic amines. GTPCH1, in fact, is the rate-limiting enzyme in BH₄ cofactor biosynthesis, which leads to a secondary impairment of neurotransmitter metabolism (both dopamine and serotonin) with or without hyperphenylalaninemias.

Unknown

AD-GTPCH1 deficiency, otherwise known as Segawa’s disease or DOPA-responsive dystonia (DRD, DYT5a), is generally characterized by normal developmental milestones until the age of 1 to 12 years. Afterwards, patients present a clinical picture characterized by lower limb dystonia. Dystonia presents diurnal fluctuations and has a clear and enduring response to L-dihydroxyphenylalanine (L-DOPA) administration. Adult onset is characterized by parkinsonism, while limb dystonia is less preminent [37, 38].

In contrast, AR-GTPCH1 deficiency presents with hyperphenylalaninemia and a severe neurological impairment characterized by developmental delay, severe cognitive impairment, seizures, limb dystonia with trunk hypotonia followed by generalized dystonia (see Chap. 21).

An intermediate autosomal recessive phenotype has also been depicted [39] presenting developmental delay and limb dystonia (with trunk hypotonia) with DOPA responsiveness.

In cases of childhood dystonia of unknown etiology, the first approach is a therapeutic trial with L-DOPA. Affected patients present a substantial and sustained response to the therapy. From a biochemical point of view, GTPCH1 catalyses the first step of BH₄ biosynthesis and enzyme dysfunction is associated to cerebrospinal fluid (CSF) biogenic amines and pterins abnormalities, with both reduction of neopterin and biopterin, which is quite typical for the disease. Hyperphenylalaninemia, in autosomal recessive variants, is found through newborn screening. Enzymatic assays and molecular genetic analysis give further information, but the CSF biochemical pattern is crucial for the diagnosis.

[18F]-FDG PET in DRD are characterized by metabolic hyperactivity in the dorsal midbrain, cerebellum, and supplementary motor area, and hypoactivity in motor and lateral premotor cortex and in the basal ganglia [40].

The clinical picture can resemble other early-onset primary dystonias (such as DYT1-related dystonia), myoclonus dystonias (like sarcoglycanopathies and DYT15 dystonia), and cerebral palsy or spastic paraparesis. Also, tyrosine hydroxylase (TH) deficiency and sepiapterin reductase (SR) deficiency, two other enzymes involved in biogenic amines metabolism, can present some kind of clinical and biochemical overlap, but differential diagnosis can be quite easily ruled out. Finally, the late-onset variant frequently presents as early-onset parkinsonism without a previous history of child-onset dystonia, so that genetic parkinsonism (for instance, PARK2 variants) and other parkinsonian-like syndromes should be excluded.

L-DOPA plus a decarboxylase inhibitor are the mainstay in the treatment of DRD, with some criticalities in recommended dosages, owing to low dose responsiveness in some patients together with severe dyskinesia side effects after higher dosage, mostly in AR-GTPCH1 intermediate deficient patients.

Typical AR-GTPCH1 deficiency with hyperphenylalaninemia needs BH₄ supplementation and neurotransmitter replacement therapy (L-DOPA and 5-hydroxytriptophan). Clinical impairment is more severe and treatment responsiveness is widely variable so that several dosage adjustments are required.

This spectrum of disorders presents a widely variable clinical impairment, ranging from a mild dystonic syndrome, highly responsive to L-DOPA treatment, to a severe neurological picture characterized by developmental delay/mental retardation, seizures, and severe dystonia with incomplete responsiveness to treatment. Even in milder forms of the disease, though the neurological picture partially links to the age of onset of symptoms (with late-onset symptomatic patients presenting a less severe phenotype), a variable responsiveness to treatment has been repeatedly underlined with a complete remission of symptoms, which is not achievable in all patients. As a whole, DRD still represents a prototype of a disease showing a dramatic positive recovery from therapy, while other disorders included in this nosological continuum need further studies to define the long-term prognosis and outcome.

Classic homocystinuria is a complex autosomal recessive disorder of methionine metabolism due to cystathionine beta synthase deficiency (CBS, OMIM 236200). A variant is pyridoxine (B6 vitamin) responsive; a second variant is non-responsive to pyridoxine. Respondent patients generally present a milder clinical phenotype.

1:100,000 births

The clinical picture is characterized by a multisystem involvement with eye, skeletal, vascular, and brain symptoms characterized by developmental delay/mental retardation, myopia and ectopia lentis, glaucoma, optic atrophy, retinal detachment and cataract, bone abnormalities, strokes, seizures, and psychiatric symptoms.

Patients present a variable clinical picture with late-onset variants showing a poorly symptomatic or acute symptomatic picture.

Amino acid analysis detects a high level of methionine in plasma and increased homocysteine in plasma and urine. Newborn screening is available with the assays of methionine and homocysteine levels. The diagnosis is then confirmed by molecular genetic testing.

Lacunar and large artery stroke can be detected (artery-to-artery embolism and dissection have also been reported) [41]. Diffuse white matter abnormalities are uncommon findings [42].

Marfan syndrome and sulfite oxydase deficiency must be excluded. The lens dislocation in homocystinuria is usually downward, while in Marfan syndrome it is upward [43]. The biochemical picture, with increased concentrations of homocystine/homocysteine or methionine, requires the exclusion of methionine transmethylation defects, methylenetetrahydrofolate reductase (MTHFR) deficiency, and cobalamin defects and other causes of homocystinuria (comprising nutritional aberrations).

Treatment is based on:

This is a good example of a treatable disorder. The life expectancy of patients with homocystinuria is reduced only if the disorder is untreated. Thromboembolism is the most common cause of death. A close biochemical and therapeutical follow-up is effective in preventing most of the symptoms with consequential good clinical prognosis and outcomes.

Fabry disease (FD, OMIM 301500) is the second most common (after Gaucher disease) progressive glycosphingolipid lysosomal storage disease [45]. It is due to an X-linked defect of lysosomal α-galoctosidase A (α-Gal A, EC3.2.1.22, OMIM 300644), resulting in accumulation of globotriaosylceramide (Gb3 or GL-3) and related glycosphingolipids (galabiosylceramide) in lysosomes of endothelial, renal, cardiac, and nerve cells. GL-3 storage starts before birth in placental tissue and progresses to organ failure (mostly heart and kidney but also gastrointestinal and respiratory systems) with multisystemic and neurological involvement (both peripheral and central nervous system are affected) [46, 47]. Fabry disease affects not only hemizygous male patients but also heterozygous females with a wide phenotypic heterogeneity.

1:3,000 – 117,000 including all variants [45].

This disorder exhibits a wide spectrum of clinical phenotypes ranging from “classical” severe phenotype in affected males up to a nearly asymptomatic presentation occasionally observed in a few heterozygous females. The first clinical signs usually present between the ages of 3 and 10 years (a few years later in girls) with peripheral somatic and autonomic nerves involvement and other signs/symptoms such as: neuropathic chronic pain or “acroparesthesias”, which may exacerbate with severe, acute, episodic crisis “Fabry crises”, abdominal pain, diarrhea or constipation, angiokeratoma, corneal changes “cornea verticillata”, retinal vessels tortuosity, tinnitus and hearing loss, minor facial dysmorphisms.

Patients display a progressive course with multisystemic involvement, which leads adulthood to: renal impairment up to renal failure; cardiac involvement (arrhythmias and left ventricular hypertrophia); cerebrovascular involvement (acute and chronic lesions); osteopenia.

Signs and symptoms are usually fully manifest in affected males while heterozygous females present a high phenotypic heterogeneity. The female spectrum includes nearly asymptomatic patients up to classic severe phenotypes presenting neuropathic pain, plus all the aforementioned clinical findings.

In both sexes, atypical variants (the most known is the cardiac variant) have also been described.

Plasma globotriaosylsphingosine or lyso-GL-3 is a useful biomarker to discern classical Fabry patients from subjects without the disease [48]. Lyso-GL-3 might correlate with white matter lesions load [49].

Brain MRI/CT – Basilar artery dolichoectasia has frequently been reported. Bilateral T1W hyperintensity is a characteristic neuroradiological sign of FD, but it is not a pathognomonic sign. Sometimes calcium deposit can be recognized in the pulvinar by CT scan. Chronic white matter abnormalities (usually symmetric) have been reported, with an increasing load according to ageing. All kinds of cerebrovascular manifestations, including cerebral venous thrombosis, can be detected [47].

Rheumatic diseases (such as rheumatic arthritis and fever, systemic lupus erythematosus, Raynaud’s phenomenon) and other small fiber peripheral neuropathies should be excluded. Mitochondrial neurogastrointestinal encephalopathy (MNGIE disease) mimics earlier aspects of Fabry disease. Later in the course of FD, multiple sclerosis, due to the white matter involvement, celiac disease, Fahr, and parathyroid disorders must be ruled out.

Since 2001, enzyme replacement therapy (ERT) with agalsidase alpha and beta has been approved in Europe as the specific treatment of FD. Recently, modified enzyme replacement and the use of active site chaperones have been proposed in patients presenting residual enzymatic activity.

Supportive drug treatment (including ACE inhibitors, antithrombotic and anticoagulant drugs) together with preventive measures (e.g., avoidance of cold that can trigger painful crisis) are recommended. Carbamazepine, gabapentin, and pregabalin are useful for neuropathic pain [46]. Renal dialysis and transplant are utilized in end-stage renal failure.

The natural history of Fabry disease is characterized by a variable, but severe clinical impairment with a later great impact on life expectancy. Before renal dialysis and transplant availability, the average age of death was 41 years in males. Renal transplants have likely changed the natural course of the disease, leading to a median lifespan of 58 years in males and 75 years in females. According to the Fabry Registry data, cardiovascular disease (usually arrhythmia) was the most common cause of death.